Recent human studies have demonstrated reduced alcohol craving and consumption in alcohol dependent patients treated with the opiate antagonist, naltrexone, relative to placebo. Given the potential of opiate antagonist modification of alcoholism, it is important to have alternative forms of antagonist available for those patients who are unable to tolerate the adverse effects of naltrexone or are excluded from treatment with naltrexone due to liver concerns. Nalmefene is an experimental opiate antagonist being studied on a pilot basis in our lab that has a number of pharmacological and clinical advantages over naltrexone. The purpose of this R01 is to demonstrate that nalmefene is a safe and effective new intervention of reducing alcohol craving and consumption in alcoholics. Additionally, repeated measures of beta endorphins, cortisol, prolactin, and LH may clarify the mechanism(s) and duration of nalmefene's clinical effects, and how alteration in these measures may relate to sobriety. This will be a double-blind study of 3 groups of 35 patients per group (total = 105). Power analyses based on outcome data from the O'Malley et al naltrexone study indicate this sample size is sufficient to test primary study hypotheses at an alpha level of .01 with beta set at .10. Patients will be randomly assigned to an oral dose of 5.0 mg (b.i.d.) nalmefene hydrochloride, 20.0 mg (b.i.d) nalmefene hydrochloride or placebo following a week long titration from 0.5 mg. In a crossover design at Week 12, patients in one treatment group will be randomly assigned in equivalent proportions to the other two treatment groups. The second treatment condition will likewise involve titration and maintenance dosing of 12 weeks duration, for a total of 24 weeks on study with a Week 36 follow-up evaluation to determine persistence of any treatment effects or whether any outcome differences emerge between groups post-treatment. Dose, study duration and outcome measures were chosen to facilitate comparison with the above naltrexone studied. Outcome variables include: % completing study, number of drinks per drinking day, number of drinking days, severity of craving, and relapse. The primary study hypotheses are: 1) Alcohol craving and consumption and rate of relapse will be significantly lower in nalmefene treated patients than placebo treated patients, and will not differ between high and low dose nalmefene patients, 2) Patients who sample alcohol while on nalmefene will have less alcohol craving and consumption and less impaired functioning than patients who drink on placebo, 3) Beta endorphin, cortisol and LH plasma levels will increase, and prolactin plasma levels decrease, significantly more in alcohol dependent patients treated with nalmefene than with placebo, 4) The hormonal levels described above will have a significant relationship to outcome in alcohol dependent patients, as defined by standardized measures of craving and drinking.